Randomized trial of oral cyclophosphamide and veliparib in high-grade serous ovarian, primary peritoneal, or fallopian tube cancers, or BRCA-mutant ovarian cancer

Shivaani Kummar, Amit M. Oza, Gini F. Fleming, Daniel M. Sullivan, David R Gandara, Michael J. Naughton, Miguel A. Villalona-Calero, Robert J. Morgan, Peter M. Szabo, Ahrim Youn, Alice P. Chen, Jiuping Ji, Deborah E. Allen, Chih Jian Lih, Michele G. Mehaffey, William D. Walsh, Paul M. McGregor, Seth M. Steinberg, P. Mickey Williams, Robert J. KindersBarbara A. Conley, Richard M. Simon, James H. Doroshow

Research output: Contribution to journalArticle

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Abstract

Purpose: Veliparib, a PARP inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase I trial. To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC). Experimental Design: Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Cross-over to the combination was allowed at disease progression. Results: Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit. Conclusion: This is the first trial that evaluated single-agent, low-dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival.

Original languageEnglish (US)
Pages (from-to)1574-1582
Number of pages9
JournalClinical Cancer Research
Volume21
Issue number7
DOIs
StatePublished - Apr 1 2015

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Fallopian Tube Neoplasms
Ovarian Neoplasms
Cyclophosphamide
Fallopian Tubes
veliparib
DNA Repair
Disease-Free Survival
Sequence Analysis
Disease Progression
Research Design
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Randomized trial of oral cyclophosphamide and veliparib in high-grade serous ovarian, primary peritoneal, or fallopian tube cancers, or BRCA-mutant ovarian cancer. / Kummar, Shivaani; Oza, Amit M.; Fleming, Gini F.; Sullivan, Daniel M.; Gandara, David R; Naughton, Michael J.; Villalona-Calero, Miguel A.; Morgan, Robert J.; Szabo, Peter M.; Youn, Ahrim; Chen, Alice P.; Ji, Jiuping; Allen, Deborah E.; Lih, Chih Jian; Mehaffey, Michele G.; Walsh, William D.; McGregor, Paul M.; Steinberg, Seth M.; Williams, P. Mickey; Kinders, Robert J.; Conley, Barbara A.; Simon, Richard M.; Doroshow, James H.

In: Clinical Cancer Research, Vol. 21, No. 7, 01.04.2015, p. 1574-1582.

Research output: Contribution to journalArticle

Kummar, S, Oza, AM, Fleming, GF, Sullivan, DM, Gandara, DR, Naughton, MJ, Villalona-Calero, MA, Morgan, RJ, Szabo, PM, Youn, A, Chen, AP, Ji, J, Allen, DE, Lih, CJ, Mehaffey, MG, Walsh, WD, McGregor, PM, Steinberg, SM, Williams, PM, Kinders, RJ, Conley, BA, Simon, RM & Doroshow, JH 2015, 'Randomized trial of oral cyclophosphamide and veliparib in high-grade serous ovarian, primary peritoneal, or fallopian tube cancers, or BRCA-mutant ovarian cancer', Clinical Cancer Research, vol. 21, no. 7, pp. 1574-1582. https://doi.org/10.1158/1078-0432.CCR-14-2565
Kummar, Shivaani ; Oza, Amit M. ; Fleming, Gini F. ; Sullivan, Daniel M. ; Gandara, David R ; Naughton, Michael J. ; Villalona-Calero, Miguel A. ; Morgan, Robert J. ; Szabo, Peter M. ; Youn, Ahrim ; Chen, Alice P. ; Ji, Jiuping ; Allen, Deborah E. ; Lih, Chih Jian ; Mehaffey, Michele G. ; Walsh, William D. ; McGregor, Paul M. ; Steinberg, Seth M. ; Williams, P. Mickey ; Kinders, Robert J. ; Conley, Barbara A. ; Simon, Richard M. ; Doroshow, James H. / Randomized trial of oral cyclophosphamide and veliparib in high-grade serous ovarian, primary peritoneal, or fallopian tube cancers, or BRCA-mutant ovarian cancer. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 7. pp. 1574-1582.
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abstract = "Purpose: Veliparib, a PARP inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase I trial. To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC). Experimental Design: Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Cross-over to the combination was allowed at disease progression. Results: Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit. Conclusion: This is the first trial that evaluated single-agent, low-dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival.",
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T1 - Randomized trial of oral cyclophosphamide and veliparib in high-grade serous ovarian, primary peritoneal, or fallopian tube cancers, or BRCA-mutant ovarian cancer

AU - Kummar, Shivaani

AU - Oza, Amit M.

AU - Fleming, Gini F.

AU - Sullivan, Daniel M.

AU - Gandara, David R

AU - Naughton, Michael J.

AU - Villalona-Calero, Miguel A.

AU - Morgan, Robert J.

AU - Szabo, Peter M.

AU - Youn, Ahrim

AU - Chen, Alice P.

AU - Ji, Jiuping

AU - Allen, Deborah E.

AU - Lih, Chih Jian

AU - Mehaffey, Michele G.

AU - Walsh, William D.

AU - McGregor, Paul M.

AU - Steinberg, Seth M.

AU - Williams, P. Mickey

AU - Kinders, Robert J.

AU - Conley, Barbara A.

AU - Simon, Richard M.

AU - Doroshow, James H.

PY - 2015/4/1

Y1 - 2015/4/1

N2 - Purpose: Veliparib, a PARP inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase I trial. To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC). Experimental Design: Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Cross-over to the combination was allowed at disease progression. Results: Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit. Conclusion: This is the first trial that evaluated single-agent, low-dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival.

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